The Skinny: An endogenous metabolite found to induce brown adipocytes
We have been working closely with Gary Siuzdak, Scripps Research Institute, to give the 2022 molecules of the month - okay, we know we missed one month but 7 out of 8 isn’t too bad! Well, after working behind the scenes, it is time to highlight some of Gary’s work.
On August 16, 2022, Gary and his collaborators, spear-headed by Carlos Guijas, published an article in Metabolites titled “Drug-initiated activity metabolomics identifies myristoylglycine as a potent endogenous metabolite for human brown fat differentiation”. This work identified myristoylglycine, a human endogenous metabolite, as a promoter of brown adipose tissue (BAT) using drug-initiated activity metabolomics (DIAM).
Obesity affects more than one-third of adults in the United States. Every state has an obesity rate of more than 20% with southern and midwestern states exhibiting the highest rates of obesity in the country. However, obesity doesn’t only affect those in the U.S. It is estimated that over 500 million adults in the world are obese and that more than 1 billion adults will be obese by 2030 if left unaddressed.
Why all the obesity statistics? Obesity results when energy intake is chronically higher than energy expenditure, where the excess energy is typically stored in the form of triglycerides in white adipose tissue (WAT). Pharmaceutical treatments of obesity have historically been aimed at reducing energy intake with few efforts aimed towards increasing energy expenditure. That is where brown adipose tissue (BAT) enters the story. Interest in BAT has been rapidly increasing as a possible target for obesity treatments. BAT activation in mice leads to increased energy expenditure, and more studies are being conducted to determine the complete role of BAT in humans and its importance in obesity.
The primary function of WAT is energy storage. BAT functions primarily to maintain body temperature by releasing heat. BAT contains lipid droplets with high levels of mitochondria expressing uncoupling protein 1 (UCP1) which upon activation causes the proton electrochemical gradient in the mitochondria to dissipate and releases heat – a process termed ‘uncoupling’ by McNeill, Suchacki, and Stimson in 2021.
Inducing BAT production and identifying related endogenous metabolites
A high-throughput screening approach led to the discovery that zafirlukast, an FDA-approved small molecule drug commonly used to treat asthma, was able to differentiate adipocyte precursors and white-biased preadipocytes into brown adipocytes.
Activity metabolomics was then used to identify endogenous metabolites that were differentially regulated upon zafirlukast dosing. Initially, from the original 30,000+ metabolic features observed, activity metabolomics allowed the list to be narrowed to 17 endogenous metabolites.
The 17 endogenous metabolites were further tested, and one proved to mimic the effects observed from zafirlukast. The metabolite, myristoylglycine, which had never previously been associated with BAT production nor any other activity. Myristoylglycine is a conjugate of myristic acid (saturated long-chain fatty acid with a 14-carbon backbone) and the amino acid glycine. Not only did myristoylglycine mimic the effects of zafirlukast, but unlike the drug, myristoylglycine had no impact on cell viability. They then took it one step further and found that treatment with zafirlukast led to the biosynthesis of myristoylglycine, possibly identifying its mode of action.
Exciting work from Gary Siuzdak, Carlos Guijas, and his team that not only showed how drug-initiated activity metabolomics can lead to a greater understanding of exogenous drug metabolism, but also gave us a pretty cool molecule of the month to share with you all. Go check out the paper and don’t forget to take a look at METLIN which helped identify it.